Between two ponds in Southampton, New York, you will find one home that looks different from all the rest. The location of Tamsen House posed a lot of environmental challenges and this design by Fernando Fisbein Architect truly rose to the occasion.[...]

There is a 50% chance that global warming will consistently exceed 1.5 degrees Celsius in the next six years, according to a new report.

Are you a senior interested in making a genuine contribution towards protecting the environment, promoting environmental sustainability, and building environmentally focused communities? Join us at the High Meadows Fellowship Info Session on Friday, November 15 from 4:30 PM - 6:00 PM in Louis A. Simpson A71 for a special opportunity to hear directly from current High Meadows Fellows about their experiences. Coffee and light refreshments will be provided. The High Meadows Fellowship Program is a generously funded fellowship opportunity that places graduating Princeton seniors in two-year positions with the nation’s leading environmental organizations. All undergraduate students are welcome to come learn about this opportunity— eligible seniors must apply by 11:59 PM on January 30, 2025.

Though there are few comps for R-rated stop-motion films at the box office, 'Memoir of a Snail' is off to an excellent start.

In the early 18th century, English criminal Jonathan Wild maintained a highly organized gang of thieves and long escaped punishment by posing as an instrument of justice and helping the authorities catch other criminals independent of, or rebellious to, his control. One such criminal was Blake, who was arrested after a burglary. He was tried, convicted, and hanged. What other notorious criminal—Blake's partner in crime—escaped from prison when Blake attacked a witness at his trial?

A look at the latest gear to cross our desks.
( Photos: 18, Comments: 88 )

An alluring scent can restore unforgettable memories, evoke emotions, rejuvenate mood, and enhance one’s presence. Luxurious fragrances expressing your personality cost an extra penny. Out of curiosity, imagine why these exclusive perfumes are way more expensive. Premium perfumes are masterpieces of pleasant aromas, luxurious packaging, and exceptional quality. Dossier perfume is an exclusive scent inspired ... Read more

The post The Art of Fragrance: The Secrets Behind the High Cost of Exclusive Perfumes appeared first on Star Two.

Photographer Zion Ozeri, whose parents immigrated to Israel from Yemen, documents the last generation of a bygone era in The Jews of Yemen – The Last Generation.

Vistors to the North Coast 500 are being asked to sign a pledge amin concerns of speeding drivers

UKHSA's Prof Susan Hopkins said respirator masks may have worked no better than thin surgical masks.

Climate change and sea ice loss leaves polar bears exposed to more diseases, research suggests.

What is behind the exodus of Economic Freedom Fighters members to ex-President Jacob Zuma's party?

Video shows a flooded terminal inside El Prat airport and partially submerged cars on a highway.

Watch highlights as undefeated Manchester United are held to a 0-0 draw by Aston Villa in the WSL.

A new FutureEd report, The Reading Revolution: How States Are Scaling Literacy Reform, tells the story of how Mississippi, Tennessee and other states at the vanguard of the reading revolution have redesigned reading instruction and raised student achievement in thousands of public schools through bold, state-level leadership. These states have addressed every aspect of early literacy, from how teachers and prospective teachers are trained to the curriculum they use, how students are assessed and whether children are retained rather than promoted to the next grade.

Shopify's surge added fuel to Canada's strong market rally, helping its benchmark index cross 25,000 for the first time.

The 2Checkout team kicked off Feb 2019 by joining over 12,000 participants in San Jose for SaaStr Annual 2019, the largest conference in the world for B2B software. The general consensus of 2Checkout team members at the end of the conference was simple and to the point: “It. Was. Amazing.”

Amid calls for ongoing protests after violent clashes on Thursday, South Africa's High Commissioner to Mozambique Siphiwe Nyanda has declared "Maputo is almost under siege".

  What if you could learn AI and Data Science based on knowledge you already know? You have an opportunity to accelerate your learning of AI in a unique way through this limited, early bird offer Here is a simple observation: The mathematical foundations of Data Science rest on four elements i.e. Linear Algebra, Probability [...]

A formal disciplinary process, or lack thereof, around the suspensions of two high-ranking officials at the National Student Financial Aid Scheme (NSFAS) has pitted Higher Education and Training Minister Nobuhle Pamela Nkabane against NSFAS administrator Freeman Nomvalo.

Neuroscientists have confirmed what every stoner already knows: music sounds better when you're high on weed. In a paper titled "Exploring the interaction between cannabis, hearing, and music," researchers from Toronto Metropolitan University reported results from a study in which participants "reported significantly greater hearing sensitivity and levels of state absorption while high compared to sober." — Read the rest

The post Music really does sound better when you're high, scientists report appeared first on Boing Boing.

Ryan Lawler notes in his Contentinople blog that CBS's high definition stream of the NCAA men's basketball tournament has been a great success.

CBS Sports reported that traffic to its NCAA March Madness on Demand site on the first day of the tourney increased 56 percent year-over-year, to 2.7 million unique users yesterday from 1.75 million uniques a year ago.

If there is a conclusion to be drawn, I do not think it is that internet video can or should compete with television. In this case, I believe the draw is a combination of the fact that watching television on Thursday afternoon is not an option for people with a day job, and that there are many games going on simultaneously and CBS television does not always cut to the game that the individual user wants to see.

I think the focus should be on the success of delivering a high quality video experience to a large audience, many of whom were at work. This is just another step in the direction of enterprise video becoming an essential element of the workplace experience.

Proteas all-rounder Marco Jansen, while acknowledging that spin has been a challenge for them in the ongoing T20 series against India, reckons things could be a bit different for Wednesday's third T20 in Centurion.

China’s high-stakes incursion in the heights of Bhutan The World Today mhiggins.drupal 28 September 2022

Why is Beijing establishing settlements over the Bhutanese border? To undermine India’s strategic security, say John Pollock and Damien Symon.

A confrontation is fomenting on the roof of the world in a country that rarely warrants international attention.

In the tiny Kingdom of Bhutan, China is building villages in isolated, mountainous regions, upping the pressure on the capital Thimphu to yield contested areas to Beijing. In doing so, China risks a collision with South Asia’s largest state and Bhutan’s principal security guarantor, India.

Sitting on top of fragile geopolitical fault lines in the Himalayas, China’s Central Military Commission has seemingly authorized a series of incursions into the Bhutanese regions of Doklam, Jakarlung, and Pasamlung. Beijing has also announced fresh claims in the east towards Sakteng. Taken together, these amount to 12 per cent of Bhutan’s total territory according to Nathan Ruser, an analyst at the Australian Strategic Policy Institute.

India is wary of Beijing’s increased assertiveness in the Himalayas following a large-scale incursion by the Chinese People’s Liberation Army (PLA) into Ladakh two years ago when dozens of Indian and Chinese soldiers were killed in a stand-off.

The appearance of Chinese roads, villages and a host of other infrastructure projects within largely uninhabited areas of Bhutan close to Tibet, have, for sections of India’s national security establishment, confirmed their worst fears – Beijing is altering the status quo across the Himalayas in a bid to undermine India’s strategic security through territorial alterations.

As a country of only 780,000 people, Bhutan is greatly influenced by New Delhi when it comes to its foreign affairs. In exchange, India guarantees the defence of the kingdom and trains the Royal Bhutanese Army. The appearance of Chinese villages on its territory risks Bhutan becoming a victim of the wider regional tensions.

The trauma of China-Bhutan border relations

Bhutan is no stranger to the territorial aspirations of its northern neighbour. Thousands of refugees fled into the country after China annexed Tibet, damaging longstanding cultural and religious links between the Tibetan and Bhutanese people – a trauma still being felt today.

Now, Beijing is laying claim to three areas within Bhutan, including Doklam in the west. This plateau is close to the Siliguri Corridor which connects to the ‘Seven Sister’ states in northeast India. Indeed, such is India’s concern over any Chinese presence near Doklam that in 2017 local Indian commanders sent troops into Bhutan to prevent PLA engineers building a road near the Doka La pass, resulting in a 72-day stand-off on Bhutanese soil between India and China, an experience Thimphu is unwilling to repeat.

Once again, China is looking to force the border issue unilaterally, altering the status quo and building villages and outposts on Bhutanese soil. On the available evidence, it has been doing so for at least three years.

The presence of Chinese villages in uninhabited areas of Bhutan serves a strategic purpose. They appear to be intended to pressure Bhutan into accepting an earlier version of a border deal that concedes Doklam to the Chinese.

Bhutan’s increasing concern is that China now views the Sino-Bhutanese border dispute as a way of unravelling India’s strategic position by stealth. Here we see a growing pattern of behaviour across the Himalayas. China is testing the boundaries in isolated and contested areas of India to attain local advantages that ensure New Delhi’s gaze remains fixed on the Himalayas.

The costly choice facing Bhutan

Bhutan for its part has very deliberately opted to remain silent, despite clear violations of its border deal with Beijing. Thimphu has made no public comment on any of the Chinese incursions.

The choice now facing Bhutan is a costly one. To concede Doklam would devastate relations with India, its closest partner. But to ignore China’s ambitions would be to risk further violations of its sovereign territory.

Bhutan may yet agree in principle to a land swap but then delay its implementation in the hope China limits any further advances. Thus Bhutan, India and China stand at a crossroads, with an impending confrontation that has not yet arrived and one that through Thimphu’s delicate diplomacy, Bhutan hopes never does.

China’s incursions into Bhutan

1. Pangda

The most high-profile incursion is in the disputed areas in Doklam. Running adjacent to the previous Doka La stand-off site, a series of Chinese projects are visible, following the Amo Chu River that runs from the Chumbi Valley in Tibet into Bhutan.

The most well-known of these xiaokang – meaning peaceful and prosperous – border projects is Pangda, a village of 124 people that sits roughly two kilometres within Bhutan from the border. First spotted by open-source intelligence analysts in October-November 2020, Chinese state media says that 27 households were moved from the Shangdui village to Pangda in September of that year and that the village is located in Yadong County, Tibet. Pangda, however, lies on territory internationally recognized as belonging to Bhutan.

Since Pangda was first identified, two more villages and an additional excavation site have been noted through satellite photographs taken in March this year, steadily following the river further into Bhutanese territory. In recent reporting by journalist Vishnu Som, a connecting road is also visible that runs 9km into Bhutan.

Given the geopolitical sensitivities of the area vis-a-vis India, speculation points to Chinese attempts to increase pressure on the Jampheri ridge overlooking the 2017 stand-off site, which according to journalist Tenzing Lamsang, is currently occupied by a small Royal Bhutanese Army detachment. As ever in the Himalayas, small tactical alterations have strategic implications. Chinese control of the Jampheri ridge would command views towards Sikkim, increase the scope of China’s surveillance operations near the border and place India’s Eastern Theatre Command at a terrain disadvantage were it to intervene as it did at Doka La.

 

2. Dramana and Shakhatoe

Further north of Doklam, at Dramana and Shakhatoe, more villages have been identified, with recent photographs taken in November 2021 showing a collection of structures nestled between snow-capped mountains. Varying in size, the largest village identified by journalist Devjyot Ghoshal comprises more than 84 buildings with construction having been started in December 2020 and seemingly completed by December 2021.

Little is known about the nature of these villages or their occupants other than their size and location. However, the Chinese PLA has patrolled these areas aggressively, warning away Bhutanese herders and challenging counter patrols by the Royal Bhutanese Army.

A permanent PLA presence in the area would be a significant change to the status quo. Informed speculation suggests that these may house either civilian contractors brought in from Tibet to oversee construction projects in the area, Tibetan or Chinese citizens brought across the border, or they could even be barracks for the PLA to help facilitate increased patrols in these contested areas.

3. Menchuma Valley

Amid the sustained activity in the west of Bhutan, we are seeing similar levels of activity mirrored in the northern contested areas in Jakarlung, Pasumlung and the Menchuma Valley, a well-known entry point into Tibet for Bhutanese pilgrims.

In May 2021, a team of researchers led by Robert Barnett from the London School of Oriental and African Studies discovered three additional villages in these contested areas, alongside a series of infrastructure projects, sitting between 3km and 5km south of the Chinese border in Bhutan. Barnett identified what appears to be police and military posts near these villages, as well as a communications tower.

While the building efforts at Doklam are seen as having a geopolitical intent towards India, these villages and their locations are seemingly aimed to maximize China’s leverage over Bhutan. They are considered sacred in Tibetan Buddhist teachings as the birthplace of ancient Himalayan cultural heroes, with strong links to the Bhutanese royal family. Today they are the home to holy sites and temples, such as the Singye Dzong.

For China to intrude on this area, and in some cases even deny entry to parts of it, is suppression of Bhutanese history, culture and traditions. By design or by default, Beijing is managing Tibetan religion and culture beyond the borders of the Tibetan Administrative Region.

 

 

 

The novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has emerged to a pandemic and caused global public health crisis. Human angiotensin-converting enzyme 2(ACE2) was identified as the entry receptor for SARS-CoV-2. As a carboxypeptidase, ACE2 cleaves many biological substrates besides angiotensin II to control vasodilatation and vascular permeability. Given the nanomolar high affinity between ACE2 and SARS-CoV-2 spike protein, we investigated how this interaction would affect the enzymatic activity of ACE2. Surprisingly, SARS-CoV-2 trimeric spike protein increased ACE2 proteolytic activity ∼3-10 fold against model peptide substrates, such as caspase-1 substrate and Bradykinin-analog. The enhancement in ACE2 enzymatic function was mediated by the binding of SARS-CoV-2 spike RBD domain. These results highlighted the potential for SARS-CoV-2 infection to enhance ACE2 activity, which may be relevant to the cardiovascular symptoms associated with COVID-19.

Ilka Wittig
Jul 1, 2007; 6:1215-1225
Research

Ivan Matic
Jan 1, 2008; 7:132-144
Research

Amelia C. Peterson
Nov 1, 2012; 11:1475-1488
Technological Innovation and Resources

Martin R. Larsen
Jul 1, 2005; 4:873-886
Technology

Staphylococcus aureus adhesion to the host's skin and mucosae enables asymptomatic colonization and the establishment of infection. This process is facilitated by cell wall-anchored adhesins that bind to host ligands. Therapeutics targeting this process could provide significant clinical benefits; however, the development of anti-adhesives requires an in-depth knowledge of adhesion-associated factors and an assay amenable to high-throughput applications. Here, we describe the development of a sensitive and robust whole cell assay to enable the large-scale profiling of S. aureus adhesion to host ligands. To validate the assay, and to gain insight into cellular factors contributing to adhesion, we profiled a sequence-defined S. aureus transposon mutant library, identifying mutants with attenuated adhesion to human-derived fibronectin, keratin, and fibrinogen. Our screening approach was validated by the identification of known adhesion-related proteins, such as the housekeeping sortase responsible for covalently linking adhesins to the cell wall. In addition, we also identified genetic loci that could represent undescribed anti-adhesive targets. To compare and contrast the genetic requirements of adhesion to each host ligand, we generated a S. aureus Genetic Adhesion Network, which identified a core gene set involved in adhesion to all three host ligands, and unique genetic signatures. In summary, this assay will enable high-throughput chemical screens to identify anti-adhesives and our findings provide insight into the target space of such an approach.

G20's lack of progress highlights challenge for COP26 Expert comment NCapeling 1 November 2021

A positive outcome from the G20 summit was committing to end international financing for coal projects but, on other issues, the communique was ultimately weak.

Success at Glasgow depends on bridging fault lines

Renata Dwan

The G20 summit’s lack of progress on climate highlights the scale of the challenge – and the stakes – for COP26.  The countries responsible for 80 per cent of global emissions recognized but failed to agree concrete action to limit global warming to 1.5C.

The leaders’ gathering reveals multilateralism’s fault lines. One is the tension between domestic politics and international priorities, reflected in the lack of ambition to reduce coal dependency.  The second is the tension between industrialized and developing states over responsibility for delivering global goods.

The G20 failed to endorse the G7’s pledge to achieve net zero emissions by 2050 or to accelerate the mobilization of previously agreed climate financing. Success at Glasgow – and beyond – will depend on the extent to which these fault lines can be bridged.

Communique’s language was weak

Professor Tim Benton

A positive outcome on climate from the G20 summit was the commitment to end international financing for coal projects by the end of 2021. This is a win for the climate and for the G20-host, Italy.

The references to 1.5 degrees and the commitment to taking further action this decade were also important, and help lay the groundwork for COP26. On the downside, the communique’s language on phasing out fossil fuel subsidies and coal domestically was very weak.

The G20 summit should be regarded as the next step – it is crucial world leaders accelerate their efforts at COP26 in Glasgow to avert climate catastrophe and keep 1.5 degrees alive.

Platitudes and vague plans on pandemic preparedness

Robert Yates

As G20 leaders head to Glasgow to tackle the evolving climate crisis, they leave Rome having failed, yet again, to take serious action to end the ongoing COVID-19 crisis.

Despite the obvious urgency to achieve universal vaccine coverage, their communique contains little more than platitudes and vague plans to prepare better for future pandemics. It is not as if they had not been briefed. 

In the run up to the G20, the leaders of the WHO, WTO, IMF, World Bank, former world leaders, Nobel laureates and the Pope, all highlighted the costs of ongoing vaccine inequity: five million deaths next year and $5.3 trillion dollars in lost economic output by 2026.

The ask was also straightforward: launch a massive airlift of unneeded vaccines from rich countries through COVAX, ramp up financing of the multilateral response and accelerate technology transfers to developing countries.

But on all these issues the wording of the communique is weak, with no numbers on vaccines or funding, no hard timescales and no urgency. This does not augur well for the COP-26 summit.

G20 communique is a launching pad

Dr Leslie Vinjamuri

The G20 might seem disappointing to some, but a lot will depend on expectations. If your starting point is a pandemic that has so far taken five million lives and driven a global economic crisis, and that both these crises are marked by deep inequality, then the measures adopted are bound to look insufficient. But if your starting point is 16 years of democracy in decline, rampant disinformation on issues of climate and public health, four years of failed international leadership during the Donald Trump presidency and, especially today, heightened tensions between the US and China, the world’s two greatest powers, then the fact that the G20 communique achieved as much as it has is remarkable.

Any written document that requires agreement between the US, UK, China, Russia, India, Saudi Arabia and the EU is necessarily going to be watered down.

But the principles are in the document, and mostly everyone turned up – if some by video. That is a good outcome for this kind of multilateralism in 2021. The G20 communique is a floor not a ceiling, and it’s a launching pad for activism and mobilisation by individual states, but also by corporates, civil society, and subnational actors. 

Now we need to hope that those on the right side of progress, whether on climate, health, or development, will use this language to drive forward concrete actions towards net zero, climate finance, vaccine distribution, and debt relief.

Specifics are for the most part missing

Creon Butler

This year’s G20 leaders’ summit marks a stark contrast with the past four years when much of the group’s energy was exhausted simply trying to maintain a consensus – in the face of opposition by a President Trump-led United States – on such issues as the importance of tackling climate change, the benefits of the rules-based multilateral trade system and the centrality of the International Monetary Fund (IMF) in the global financial safety net. 

By contrast, today’s G20 Rome Leaders’ declaration early on underlines ‘the crucial role of multilateralism in finding shared, effective solutions’. In two critical areas for the world economy – the global boost to liquidity from the general allocation of $650bn in Special Drawing Rights and the global tax deal focused on addressing challenges arising from digitalisation – this outlook has been translated into very substantial and concrete achievements announced earlier in the year.

Alzheimer's disease (AD) is characterized by neuronal loss and accumulation of β-amyloid-protein (Aβ) in the brain parenchyma. Sleep impairment is associated with AD and affects about 25–40% of patients in the mild-to-moderate stages of the disease. Sleep deprivation leads to increased Aβ production; however, its mechanism remains largely unknown. We hypothesized that the increase in core body temperature induced by sleep deprivation may promote Aβ production. Here, we report temperature-dependent regulation of Aβ production. We found that an increase in temperature, from 37 °C to 39 °C, significantly increased Aβ production in amyloid precursor protein-overexpressing cells. We also found that high temperature (39 °C) significantly increased the expression levels of heat shock protein 90 (Hsp90) and the C-terminal fragment of presenilin 1 (PS1-CTF) and promoted γ-secretase complex formation. Interestingly, Hsp90 was associated with the components of the premature γ-secretase complex, anterior pharynx-defective-1 (APH-1), and nicastrin (NCT) but was not associated with PS1-CTF or presenilin enhancer-2. Hsp90 knockdown abolished the increased level of Aβ production and the increased formation of the γ-secretase complex at high temperature in culture. Furthermore, with in vivo experiments, we observed increases in the levels of Hsp90, PS1-CTF, NCT, and the γ-secretase complex in the cortex of mice housed at higher room temperature (30 °C) compared with those housed at standard room temperature (23 °C). Our results suggest that high temperature regulates Aβ production by modulating γ-secretase complex formation through the binding of Hsp90 to NCT/APH-1.

Mohamad Navab
Sep 1, 2000; 41:1495-1508
Articles

Mohamad Navab
Sep 1, 2000; 41:1481-1494
Articles

S Eisenberg
Oct 1, 1984; 25:1017-1058
Reviews

Vitali Matyash
May 1, 2008; 49:1137-1146
Methods

Buyang Li, Zongze Yang and Zhi Zhou
Math. Comp. 93 (), 2557-2586.
Abstract, references and article information

Ralph M. Kaufmann, Martin Markl and Alexander A. Voronov, editors. American Mathematical Society, 2024, CONM, volume 802, approx. 330 pp. ISBN: 978-1-4704-7142-2 (print), 978-1-4704-7642-7 (online). This volume contains the proceedings of the AMS Special Session on Higher Structures in Topology, Geometry, and Physics, held virtually on March...

Paweł Hitczenko and Nick Wormald
Proc. Amer. Math. Soc. 152 (), 5411-5427.
Abstract, references and article information

Ferdinand Ihringer
Proc. Amer. Math. Soc. 152 (), 5355-5365.
Abstract, references and article information

Dylan Langharst and Dongmeng Xi
Proc. Amer. Math. Soc. 152 (), 5299-5311.
Abstract, references and article information

Jan Draisma and Thomas Karam
Proc. Amer. Math. Soc. 152 (), 5083-5093.
Abstract, references and article information

Zhanqiang Bai, Jia-Jun Ma, Wei Xiao and Xun Xie
Represent. Theory 28 (), 498-513.
Abstract, references and article information

Family, friends, and community members gathered on Saturday at the Falmouth First Assembly Church to celebrate the life of 15-year-old Jahmarie Reid, a William Knibb High student who tragically lost his life at sea on August 27 in what is believed...

The dimeric ectonucleotidase CD73 catalyzes the hydrolysis of AMP at the cell surface to form adenosine, a potent suppressor of the immune response. Blocking CD73 activity in the tumor microenvironment can have a beneficial effect on tumor eradication and is a promising approach for cancer therapy. Biparatopic antibodies binding different regions of CD73 may be a means to antagonize its enzymatic activity. A panel of biparatopic antibodies representing the pairwise combination of 11 parental monoclonal antibodies against CD73 was generated by Fab-arm exchange. Nine variants vastly exceeded the potency of their parental antibodies with ≥90% inhibition of activity and subnanomolar EC50 values. Pairing the Fabs of parents with nonoverlapping epitopes was both sufficient and necessary whereas monovalent antibodies were poor inhibitors. Some parental antibodies yielded potent biparatopics with multiple partners, one of which (TB19) producing the most potent. The structure of the TB19 Fab with CD73 reveals that it blocks alignment of the N- and C-terminal CD73 domains necessary for catalysis. A separate structure of CD73 with a Fab (TB38) which complements TB19 in a particularly potent biparatopic shows its binding to a nonoverlapping site on the CD73 N-terminal domain. Structural modeling demonstrates a TB19/TB38 biparatopic antibody would be unable to bind the CD73 dimer in a bivalent manner, implicating crosslinking of separate CD73 dimers in its mechanism of action. This ability of a biparatopic antibody to both crosslink CD73 dimers and fix them in an inactive conformation thus represents a highly effective mechanism for the inhibition of CD73 activity.

Abnormal changes of neuronal Tau protein, such as phosphorylation and aggregation, are considered hallmarks of cognitive deficits in Alzheimer's disease. Abnormal phosphorylation is thought to precede aggregation and therefore to promote aggregation, but the nature and extent of phosphorylation remain ill-defined. Tau contains ∼85 potential phosphorylation sites, which can be phosphorylated by various kinases because the unfolded structure of Tau makes them accessible. However, methodological limitations (e.g. in MS of phosphopeptides, or antibodies against phosphoepitopes) led to conflicting results regarding the extent of Tau phosphorylation in cells. Here we present results from a new approach based on native MS of intact Tau expressed in eukaryotic cells (Sf9). The extent of phosphorylation is heterogeneous, up to ∼20 phosphates per molecule distributed over 51 sites. The medium phosphorylated fraction Pm showed overall occupancies of ∼8 Pi (± 5) with a bell-shaped distribution; the highly phosphorylated fraction Ph had 14 Pi (± 6). The distribution of sites was highly asymmetric (with 71% of all P-sites in the C-terminal half of Tau). All sites were on Ser or Thr residues, but none were on Tyr. Other known posttranslational modifications were near or below our detection limit (e.g. acetylation, ubiquitination). These findings suggest that normal cellular Tau shows a remarkably high extent of phosphorylation, whereas other modifications are nearly absent. This implies that abnormal phosphorylations at certain sites may not affect the extent of phosphorylation significantly and do not represent hyperphosphorylation. By implication, the pathological aggregation of Tau is not likely a consequence of high phosphorylation.

Visual Abstract

Jessica Y. Franco
Dec 1, 2020; 19:1936-1951
Research

Toma Keser
Dec 29, 2020; 0:RA120.002433v1-mcp.RA120.002433
Research

Juntuo Zhou
Nov 30, 2020; 0:RA120.002384v1-mcp.RA120.002384
Research